Efficacy, toxicity, pharmacokinetics, and in vitro metabolism of the enantiomers of ifosfamide in mice.
The enantiomers of the anticancer drug ifosfamide, (+)-(R)-IFF and (-)-(S)-IFF, were prepared from the racemic compound rac-IFF using enantioselective liquid chromatographic techniques. The efficacy, toxicity, and pharmacokinetics of the individual enantiomers and rac-IFF were studied in mice. The results of the studies indicate that there were no statistically significant differences between the efficacy of (+)-(R)-IFF, (-)-(S)-IFF, and rac-IFF against childhood rhabdomyosarcoma (HxRh28) maintained in vivo as a xenograft in immune-deprived female CBA/CaJ mice. Similar results were found in toxicity and pharmacokinetic studies conducted in non-tumor-bearing female CBA/CaJ mice. The production of two major metabolites, aldoifosfamide and isophosphoramide mustard, by mice hepatic microsomes from non-tumor-bearing female CBA/CaJ mice was also investigated. There were no statistically significant differences in the calculated kinetic parameters, Vmax and Km, of the production of these two metabolites when the separate enantiomers or the racemic mixture were used as substrate.
Masurel
D
D
Department of Pharmacokinetics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
Houghton
P J
PJ
Young
C L
CL
Wainer
I W
IW
D000818:Animals; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000031:analogs & derivatives / Q000378:metabolism* / Q000627:therapeutic use / Q000633:toxicity; D066298:In Vitro Techniques; D051379:Mice; D008808:Mice, Inbred CBA; D008862:Microsomes, Liver / Q000378:metabolism; D009368:Neoplasm Transplantation; D010752:Phosphoramide Mustards; D012208:Rhabdomyosarcoma / Q000188:drug therapy; D013237:Stereoisomerism; D014183:Transplantation, Heterologous
D010752:Phosphoramide Mustards; C027061:isophosphamide mustard; D007069:Ifosfamide